EP4028445A1 - Fibrous materials - Google Patents

Fibrous materials

Info

Publication number
EP4028445A1
EP4028445A1 EP20771296.9A EP20771296A EP4028445A1 EP 4028445 A1 EP4028445 A1 EP 4028445A1 EP 20771296 A EP20771296 A EP 20771296A EP 4028445 A1 EP4028445 A1 EP 4028445A1
Authority
EP
European Patent Office
Prior art keywords
cup
mol
peg
fibrous material
cross
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP20771296.9A
Other languages
German (de)
French (fr)
Other versions
EP4028445B1 (en
Inventor
Arn MIGNON
Tom Gheysens
Sandra VAN VLIERBERGHE
Peter Dubruel
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Universiteit Gent
Original Assignee
Universiteit Gent
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Filing date
Publication date
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Publication of EP4028445A1 publication Critical patent/EP4028445A1/en
Application granted granted Critical
Publication of EP4028445B1 publication Critical patent/EP4028445B1/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G18/00—Polymeric products of isocyanates or isothiocyanates
    • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
    • C08G18/70—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the isocyanates or isothiocyanates used
    • C08G18/72—Polyisocyanates or polyisothiocyanates
    • C08G18/74—Polyisocyanates or polyisothiocyanates cyclic
    • C08G18/75—Polyisocyanates or polyisothiocyanates cyclic cycloaliphatic
    • C08G18/751—Polyisocyanates or polyisothiocyanates cyclic cycloaliphatic containing only one cycloaliphatic ring
    • C08G18/752—Polyisocyanates or polyisothiocyanates cyclic cycloaliphatic containing only one cycloaliphatic ring containing at least one isocyanate or isothiocyanate group linked to the cycloaliphatic ring by means of an aliphatic group
    • C08G18/753—Polyisocyanates or polyisothiocyanates cyclic cycloaliphatic containing only one cycloaliphatic ring containing at least one isocyanate or isothiocyanate group linked to the cycloaliphatic ring by means of an aliphatic group containing one isocyanate or isothiocyanate group linked to the cycloaliphatic ring by means of an aliphatic group having a primary carbon atom next to the isocyanate or isothiocyanate group
    • C08G18/755—Polyisocyanates or polyisothiocyanates cyclic cycloaliphatic containing only one cycloaliphatic ring containing at least one isocyanate or isothiocyanate group linked to the cycloaliphatic ring by means of an aliphatic group containing one isocyanate or isothiocyanate group linked to the cycloaliphatic ring by means of an aliphatic group having a primary carbon atom next to the isocyanate or isothiocyanate group and at least one isocyanate or isothiocyanate group linked to a secondary carbon atom of the cycloaliphatic ring, e.g. isophorone diisocyanate
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D67/00—Processes specially adapted for manufacturing semi-permeable membranes for separation processes or apparatus
    • B01D67/0002—Organic membrane manufacture
    • B01D67/0004—Organic membrane manufacture by agglomeration of particles
    • B01D67/00042—Organic membrane manufacture by agglomeration of particles by deposition of fibres, nanofibres or nanofibrils
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D71/00—Semi-permeable membranes for separation processes or apparatus characterised by the material; Manufacturing processes specially adapted therefor
    • B01D71/06—Organic material
    • B01D71/54—Polyureas; Polyurethanes
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F290/00—Macromolecular compounds obtained by polymerising monomers on to polymers modified by introduction of aliphatic unsaturated end or side groups
    • C08F290/02—Macromolecular compounds obtained by polymerising monomers on to polymers modified by introduction of aliphatic unsaturated end or side groups on to polymers modified by introduction of unsaturated end groups
    • C08F290/06—Polymers provided for in subclass C08G
    • C08F290/067—Polyurethanes; Polyureas
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G18/00—Polymeric products of isocyanates or isothiocyanates
    • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
    • C08G18/28—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the compounds used containing active hydrogen
    • C08G18/40—High-molecular-weight compounds
    • C08G18/42—Polycondensates having carboxylic or carbonic ester groups in the main chain
    • C08G18/4266—Polycondensates having carboxylic or carbonic ester groups in the main chain prepared from hydroxycarboxylic acids and/or lactones
    • C08G18/4269—Lactones
    • C08G18/4277—Caprolactone and/or substituted caprolactone
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G18/00—Polymeric products of isocyanates or isothiocyanates
    • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
    • C08G18/28—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the compounds used containing active hydrogen
    • C08G18/40—High-molecular-weight compounds
    • C08G18/42—Polycondensates having carboxylic or carbonic ester groups in the main chain
    • C08G18/4266—Polycondensates having carboxylic or carbonic ester groups in the main chain prepared from hydroxycarboxylic acids and/or lactones
    • C08G18/4283—Hydroxycarboxylic acid or ester
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G18/00—Polymeric products of isocyanates or isothiocyanates
    • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
    • C08G18/28—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the compounds used containing active hydrogen
    • C08G18/40—High-molecular-weight compounds
    • C08G18/48—Polyethers
    • C08G18/4833—Polyethers containing oxyethylene units
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G18/00—Polymeric products of isocyanates or isothiocyanates
    • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
    • C08G18/28—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the compounds used containing active hydrogen
    • C08G18/40—High-molecular-weight compounds
    • C08G18/62—Polymers of compounds having carbon-to-carbon double bonds
    • C08G18/6204—Polymers of olefins
    • C08G18/6208—Hydrogenated polymers of conjugated dienes
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G18/00—Polymeric products of isocyanates or isothiocyanates
    • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
    • C08G18/28—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the compounds used containing active hydrogen
    • C08G18/67—Unsaturated compounds having active hydrogen
    • C08G18/671—Unsaturated compounds having only one group containing active hydrogen
    • C08G18/672—Esters of acrylic or alkyl acrylic acid having only one group containing active hydrogen
    • C08G18/6725—Esters of acrylic or alkyl acrylic acid having only one group containing active hydrogen containing ester groups other than acrylate or alkylacrylate ester groups
    • D—TEXTILES; PAPER
    • D01—NATURAL OR MAN-MADE THREADS OR FIBRES; SPINNING
    • D01D—MECHANICAL METHODS OR APPARATUS IN THE MANUFACTURE OF ARTIFICIAL FILAMENTS, THREADS, FIBRES, BRISTLES OR RIBBONS
    • D01D5/00—Formation of filaments, threads, or the like
    • D01D5/0007—Electro-spinning
    • D01D5/0015—Electro-spinning characterised by the initial state of the material
    • D01D5/003—Electro-spinning characterised by the initial state of the material the material being a polymer solution or dispersion
    • D01D5/0038—Electro-spinning characterised by the initial state of the material the material being a polymer solution or dispersion the fibre formed by solvent evaporation, i.e. dry electro-spinning
    • D—TEXTILES; PAPER
    • D01—NATURAL OR MAN-MADE THREADS OR FIBRES; SPINNING
    • D01F—CHEMICAL FEATURES IN THE MANUFACTURE OF ARTIFICIAL FILAMENTS, THREADS, FIBRES, BRISTLES OR RIBBONS; APPARATUS SPECIALLY ADAPTED FOR THE MANUFACTURE OF CARBON FILAMENTS
    • D01F1/00—General methods for the manufacture of artificial filaments or the like
    • D01F1/02—Addition of substances to the spinning solution or to the melt
    • D01F1/10—Other agents for modifying properties
    • D01F1/103—Agents inhibiting growth of microorganisms
    • D—TEXTILES; PAPER
    • D01—NATURAL OR MAN-MADE THREADS OR FIBRES; SPINNING
    • D01F—CHEMICAL FEATURES IN THE MANUFACTURE OF ARTIFICIAL FILAMENTS, THREADS, FIBRES, BRISTLES OR RIBBONS; APPARATUS SPECIALLY ADAPTED FOR THE MANUFACTURE OF CARBON FILAMENTS
    • D01F6/00—Monocomponent artificial filaments or the like of synthetic polymers; Manufacture thereof
    • D01F6/58—Monocomponent artificial filaments or the like of synthetic polymers; Manufacture thereof from homopolycondensation products
    • D01F6/70—Monocomponent artificial filaments or the like of synthetic polymers; Manufacture thereof from homopolycondensation products from polyurethanes
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D2239/00—Aspects relating to filtering material for liquid or gaseous fluids
    • B01D2239/02—Types of fibres, filaments or particles, self-supporting or supported materials
    • B01D2239/0291—Types of fibres, filaments or particles, self-supporting or supported materials comprising swelling polymers
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G2210/00—Compositions for preparing hydrogels
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G2340/00—Filter material
    • D—TEXTILES; PAPER
    • D01—NATURAL OR MAN-MADE THREADS OR FIBRES; SPINNING
    • D01D—MECHANICAL METHODS OR APPARATUS IN THE MANUFACTURE OF ARTIFICIAL FILAMENTS, THREADS, FIBRES, BRISTLES OR RIBBONS
    • D01D5/00—Formation of filaments, threads, or the like
    • D01D5/0007—Electro-spinning
    • D01D5/0015—Electro-spinning characterised by the initial state of the material
    • D01D5/003—Electro-spinning characterised by the initial state of the material the material being a polymer solution or dispersion

Definitions

  • the present invention relates to the field of fibrous materials, more in particular comprising a cross- linkable urethane-based polymer (CUP) and an oligomeric or macromonomeric urethane-based cross-linker.
  • CUP cross- linkable urethane-based polymer
  • the present invention also provides uses of such fibrous materials, such as for example as a hydrogel, in filtration devices, in affinity membranes, in (protective) clothing, in drug delivery systems, in tissue scaffolds, etc. It further provides the fibrous materials as defined herein for use in human and/or veterinary medicine, such as for use in skin and/or wound care.
  • micro/nanomaterials have emerged as useful components in various applications, ranging from medical applications over environmental applications (e.g. filtration) even up to the use in safety devices, such as in (protective) clothing.
  • the reason for this, is that micro/nanomaterials have unusual properties compared to macro-sized materials, due to their micro/nanoscale dimensions. In particular, they have extraordinary high surface area-to-volume ratios, and they can be tunable.
  • Micro/nanomaterials are often composed of fibers having micro/nanoscale diameters, in the form of micro/nanofibers.
  • Such micro/nanofibers can be produced using a variety of techniques, including template synthesis, phase separation, self-assembly, electrospinning, etc.
  • Electrospinning is a particularly suitable fiber production method that uses electric forces to draw charged threads of polymer solutions or polymer melts up to fiber diameters in the order of some hundred micro/nanometers.
  • the process does not require the use of coagulation chemistry or high temperatures to produce solid threads from solution. This makes the process particularly suited to the production of (micro/nano) fibers using large and complex molecules.
  • Micro/nanofiber matrices can have numerous applications particularly in the biomedical field such as for wound dressings or tissue scaffolds.
  • Such electrospun dressings and scaffolds have exceptionally high surface areas and porosities because they are comprised of fibers with micro/nanoscale diameters, thereby enabling them to encourage superior cell infiltration, adhesion and efflux of liquids.
  • Electrospinning has the disadvantage however, that often toxic solvents are needed and that it is highly dependent on the starting materials to obtain the desired results.
  • Starting materials that are particularly preferable for use in electrospinning (or other fiber production methods) should be processable, spinnable, non-shrinkable and stable. It is in particular difficult to select components having hydrogel properties, while still being easily processable and/or stabilized into fibers. It was thus an object of the present invention to provide a solution to the above-stated problems.
  • CUP cross-linkable urethane-based polymer
  • an oligomeric or macromonomeric urethane-based cross-linker is particularly suitable in the preparation of fibrous materials via electrospinning, or other methods for preparing micro/nanofibers. It was specifically found that a combination of high molecular weight and low molecular weight CUPs is particularly suitable for said purpose.
  • the present invention provides a fibrous material comprising:
  • CUP cross-linkable urethane-based polymer
  • X and Y is independently a moiety comprising one or more of the following: acrylate groups, (multi)methacrylate groups, (multi)acrylate group, thiolactones and thiol-ene crosslinkable groups
  • each occurrence of Spacer is independently selected from the list comprising: oligo(ethylene oxide), oligo(propylene oxide), oligo(caprolactone), oligo(lactide) and oligo(glycolide)
  • the present invention provides a fibrous material comprising:
  • an oligomeric or macromonomeric urethane-based cross-linker having a backbone molecular weight of less than or equal to 2000 g/mol
  • CUP cross-linkable urethane-based polymer represented by formula (I) and having a backbone molecular weight of above 2000 g/mol; wherein each occurrence of X and Y is independently a moiety comprising one or more of the following: acrylate groups, (multi)methacrylate groups, (multi)acrylate group, thiolactones and thiol-ene crosslinkable groups; each occurrence of Spacer is independently selected from the list comprising: oligo(ethylene oxide), oligo(propylene oxide), oligo(caprolactone), oligo(lactide) and oligo(glycolide); m and n are each independent from 1-6; p is from 1-10; and each occurrence of Backbone is independently selected from the list comprising poly(ethylene glycol) (PEG), poly(vinyl pyrrolidone) (PVP), poly(N-vinyl caprolactam) (PNVCL), poly(caprolactone) (POL
  • At least one occurrence of said Backbone is PEG; in particular PEG having a molecular weight of above 10000 g/mol (PEG10k); more in particular PEG 12k, PEG20k, PEG35k or PEG40k; preferably PEG20k.
  • said urethane-based crosslinker has a backbone selected from the list comprising PEG, multi-(meth)acrylate or multi-(meth)acrylamide or a thiol-ene crosslinkable group; in particular said crosslinker is a cross-linkable urethane-based polymer (CUP) represented by formula (I), wherein PEG has a molecular weight of about 400 g/mol (CUP-PEG400) to about 2000 g/mol (CUP-PEG2k).
  • CUP cross-linkable urethane-based polymer
  • the weight ratio of said CUP to crosslinker is between 90:10 and 60:40; preferably 90:10.
  • the present invention provides a fibrous material comprising:
  • CUP cross-linkable urethane-based polymer represented by formula (I), wherein PEG has a molecular weight of above 10000 g/mol;
  • a cross-linkable urethane-based polymer represented by formula (I), wherein PEG has a molecular weight of about 400 g/mol (CUP-PEG400) to about 2000 g/mol (CUP-PEG2k).
  • CUP-PEG400 a cross-linkable urethane-based polymer represented by formula (I)
  • PEG has a molecular weight of about 400 g/mol (CUP-PEG400) to about 2000 g/mol (CUP-PEG2k).
  • the present invention provides a fibrous material comprising:
  • CUP cross-linkable urethane-based polymer represented by formula (I), wherein PEG has a molecular weight of about 20000 g/mol (CUP-PEG20k);
  • CUP cross-linkable urethane-based polymer represented by formula (I), wherein PEG has a molecular weight of about 2000 g/mol (CUP-PEG2k).
  • the weight ratio of said CUP-PEG20k to CUP- PEG2k is 90:10.
  • the fibrous material of the present invention may further comprise an active agent.
  • the fibrous material may be chemically crosslinked.
  • the present invention also provides the use of the fibrous material as defined herein; as a hydrogel, in filtration devices, in affinity membranes, in (protective) clothing, in drug delivery systems, in tissue scaffolds.
  • the present invention further provides the fibrous material as defined herein for use in human and/or veterinary medicine; in particular for use in skin care and/or wound care.
  • the present invention also provides a fibrous material as defined herein for use in human and/or veterinary medicine; more in particular for use in skin care and/or wound care.
  • the present invention provides a fibrous material comprising:
  • each occurrence of X and Y is independently a moiety comprising one or more of the following: acrylate groups, (multi)methacrylate groups, (multi)acrylate group, thiolactones and thiol-ene crosslinkable groups; each occurrence of Spacer is independently selected from the list comprising: oligo(ethylene oxide), oligo(propylene oxide), oligo(caprolactone), oligo(lactide) and oligo(glycolide); m and n are each independently from 1-6; p is from 1-10; and each occurrence of Backbone is independently selected from the list comprising poly(ethylene glycol) (PEG), poly(vinyl pyrrolidone) (PVP), poly(N-vinyl caprolactam) (PNVCL), poly(caprolactone) (POL), poly(lactic acid) (PLA) or a combination thereof.
  • PEG poly(vinyl pyrrolidone)
  • PVP poly(N-vinyl caprol
  • the present invention provides a fibrous material comprising:
  • an oligomeric or macromonomeric urethane-based cross-linker having a backbone molecular weight of less than or equal to 2000 g/mol
  • CUP cross-linkable urethane-based polymer represented by formula (I) and having a backbone molecular weight of above 2000 g/mol wherein each occurrence of X and Y is independently a moiety comprising one or more of the following: acrylate groups, (multi)methacrylate groups, (multi)acrylate group, thiolactones and thiol-ene crosslinkable groups; each occurrence of Spacer is independently selected from the list comprising: oligo(ethylene oxide), oligo(propylene oxide), oligo(caprolactone), oligo(lactide) and oligo(glycolide); m and n are each independent from 1-6; p is from 1-10; and each occurrence of Backbone is independently selected from the list comprising poly(ethylene glycol) (PEG), poly(vinyl pyrrolidone) (PVP), poly(N-vinyl caprolactam) (PNVCL), poly(caprolactone) (POL),
  • PEG poly
  • urethane-based polymer is meant to be a polymeric agent containing one or more carbamate or urethane links.
  • a carbamate is an organic compound derived from carbamic acid (NH2COOH), and as such a carbamate link may be generally represented as follows: wherein each of said represents an attachment point to the remainder of the polymer molecule.
  • the claimed polymers contain at least one carbamate linker, however, they may also contain several carbamate linkers such as 2, 3, 4, or 5 carbamates.
  • this moiety may contain only urethane linkers.
  • this moiety may contain only urea linkers.
  • this moiety may also contain a combination of urethane and urea linkers.
  • the urethane-based polymers of the present invention may include different types and numbers of end-groups, including acrylate groups, (multi)methacrylate groups, (multi)acrylate group, thiolactones and thiol-ene crosslinkable groups.
  • the urethane- based polymers may also include (meth)acrylamide groups.
  • the compounds of the present invention may also be termed as such, for example, in the event of X and/or Y being selected as acrylate groups, the polymers may be termed acrylate end-capped urethane-based polymers (i.e. AUP).
  • the present invention also provides an acrylate end-capped urethane-based polymer of formula (II)
  • the present invention also provides a urethane-based polymer of formula (I) wherein m, n, p, Spacer and Backbone are defined as herein above.
  • a urethane-based polymer of formula (I) wherein m, n, p, Spacer and Backbone are defined as herein above.
  • acrylate end-capped as used herein means that the acrylate groups of the molecules of the invention are the polymer endgroups.
  • acrylate is meant to include salts, esters and conjugate bases of acrylic acid and it derivatives.
  • Acrylates contain vinyl groups, i.e. 2 carbon atoms double bonded to each other, directly attached to a carbonyl carbon.
  • An acrylate moiety is typically represented as follows: wherein R represents -H in the event of acrylates or an alkyl group such as for example a methyl (-CH3) moiety, in the event of methacrylates.
  • the (meth)acrylate groups according to the present invention are attached to the remainder of the polymer via the -O- linker, such that the double bonded carbon atom faces outwardly of the molecules.
  • X and/or Y may be selected to be a functional group that is able to or susceptible to thiol-ene cross-linking (i.e. a thiol-ene cross-linkable group).
  • the functional groups comprise functional groups able to or susceptible to thiol-ene crosslinking.
  • the functional groups comprise for example meth(acrylate) functional groups, norbornene functional groups, vinyl ether functional groups, vinylester functional groups, allyl ether functional groups, propenyl ether functional groups and/or alkene functional groups and/or N-vinylamide functional groups.
  • Particularly preferred functional groups comprise norbornene functional groups and/or vinylether functional groups.
  • thiol-ene cross-linkable groups in the urethane-based polymers of the present invention, may be advantageous, since these can reduce the brittleness of the end products and result in a more homogeneous network formation.
  • spacer is meant to be a moiety intended to provide a (flexible) hinge between 2 other elements of the molecule in which it is included, thereby spatially separating said elements.
  • a spacer may be present as indicated in Formula I.
  • any type of suitable moiety may be used as a spacer, however, it is preferably selected from the list comprising oligo(ethylene oxide), oligo(propylene oxide), oligo(caprolactone), oligo(lactide) and oligo(glycolide):
  • the spacer is present on both sides of the molecule, in which m and n are independently selected from 1-6.
  • a spacer is selected to be for example oligo(ethylene oxide) and n is for example 2, the spacer thus comprises 2 ethylene oxide moieties.
  • the left and right parts of the claimed molecules need not to be symmetrical, meaning that each spacer and the number of monomeric units within each spacer may be selected independently from each other. Nevertheless, in a preferred embodiment, the left and right parts of the claimed molecules are symmetrical, meaning that both sides of the molecule contain the same spacer containing the same number of monomeric units.
  • the claimed molecules also encompass a backbone, which may be selected from the list comprising: poly(ethylene glycol) (PEG), poly(vinyl pyrrolidone) (PVP), poly(n- vinyl caprolactam) (PNVCL), poly(lactic acid) (PLA), poly(caprolactone) (PCL) or a combination thereof: poly(lactic acid) (PLA) poly(caprolactone)
  • a backbone which may be selected from the list comprising: poly(ethylene glycol) (PEG), poly(vinyl pyrrolidone) (PVP), poly(n- vinyl caprolactam) (PNVCL), poly(lactic acid) (PLA), poly(caprolactone) (PCL) or a combination thereof: poly(lactic acid) (PLA) poly(caprolactone)
  • the present invention provides a polymer combination of cross-linkable urethane-based polymers (CUPs) represented by formula (I) and/or formula (II); wherein at least one of said polymers has a backbone of PEG and at least one other polymer has a backbone of PVP, PNVCL, PLA, PCL or a combination thereof.
  • said polymer combination may be selected from a copolymer, a polymer blend, or a combination of different polymer layers (i.e. multilayer stack).
  • polymer blend is meant to be a polymer mixture in which two or more polymers of a different nature are blended.
  • a copolymer is meant to be a polymeric molecule comprising at least 2 different types of monomeric subunits.
  • CUP cross-linkable urethane- based polymer represented by formula (I); wherein at least one part of said polymer has a backbone of PEG and at least one other part of said polymer has a backbone of PVP, PNVCL, PLA, PCL or a combination thereof.
  • the cross-linker is selected such as to have a low molecular weight, whereas the CUP is preferably having a higher molecular weight.
  • said cross-linker has a molecular weight of less than or equal to 2000 g/mol; such as from about 400 g/mol to about 2000 g/mol; more specifically about 400 g/mol; about 500 g/mol; about 600 g/mol; about 700 g/mol; about 800 g/mol; about 900 g/mol; about 1000 g/mol; about 1100 g/mol; about 1200 g/mol; about 1300 g/mol; about 1400 g/mol; about 1500 g/mol; about 1600 g/mol; about 1700 g/mol; about 1800 g/mol; about 1900 g/mol; or about 2000 g/mol.
  • said CUP has a molecular weight of above 2000 g/mol; such as about 4.000 g/mol; about 6.000 g/mol; about 8.000 g/mol; about 10.000 g/mol; about 12.000 g/mol, about 20.000 g/mol, about 35.000 g/mol, about 40.000 g/mol.
  • the crosslinker is preferably having a low molecular weight, i.e. less than or equal to 2000 g/mol (e.g. 400 g/mol - 2000 g/mol) and the polymer is preferably having a high molecular weight, i.e. above 2000 g/mol (e.g. > 10000 g/mol, preferably > 20000 g/mol).
  • said backbone has a molecular weight of about 400 g/mol to about 40000 g/mol.
  • the crosslinker is preferably selected to have a backbone with a low molecular weight (e.g. 400 g/mol - 2000 g/mol) and the polymer is preferably selected to have a backbone with a high molecular weight (e.g. > 10000 g/mol, preferably > 20000 g/mol).
  • molecular weight in respect of a polymer is used, this is meant to be the molecular weight of the backbone. Accordingly, where a polymer is said to have a molecular weight of above 2.000 g/mol; it is meant that the backbone of said polymer should have a molecular weight of above 2.000 g/mol.
  • the backbone of the polymers and if applicable the crosslinkers may be selected from any PEG, any PVP, any PNVCL, any PLA, any PCL or any combination thereof, such as a combination of PEG and PVP, a combination of PEG and PNVCL, a combination of PEG and PCL, a combination of PEG and PLA, etc.
  • Each of said combinations may thus be in the form of a polymer blend, e.g. polymers having a PEG backbone blended together with polymers having a PVP backbone.
  • said combinations may be in the form of a copolymer, e.g.
  • polymers having a PEG/PVP backbone wherein some occurrences of Backbone are selected to be PEG and other occurrences of Backbone are selected to be PVP.
  • PEG/PNVCL PEG/PLA
  • PEG/PCL PEG/PCL
  • At least one occurrence of said Backbone is PEG; in particular PEG having a molecular weight of above 10000 g/mol; more in particular PEG 12k, PEG20k, PEG35k or PEG40k; preferably PEG20k.
  • the advantage of the CUPs of the present invention is that they are electrospinnable. This is particularly advantageous in that these electrospun materials can be made in any kind of format, such as for example in the form of a sheet, a membrane, a fiber, a particle, a scaffold, etc. Electrospun materials provide an excellent environment to promote wound healing. Micro/nanofibers generated by the electrospinning technique offer a high surface-to-volume ratio, show good porosity levels, allow gaseous exchange and mimic the natural extra-cellular matrix. The formation of fibers via electrospinning depends on several parameters including but not limited to the viscosity, the needle-to-collector distance, the flow rate and the applied voltage, etc. These parameters influence the morphology of the obtained fibers.
  • Cross-linkable urethane-based polymers are very interesting in this respect, due to their ability to cross-link upon Ultra-Violet (UV) irradiation in solid state. In addition, they exhibit high mechanical strength (up to 0.6 MPa in swollen state for precursors cross-linked in a 30 wt% aqueous solution) and biocompatibility.
  • These hydrogel precursors can be based on different polymer backbones and cross-linking in the solid state is promoted by the presence of a flexible spacer which is linked to the backbone polymer by means of a di-isocyanate (such as for example isophorone di-isocyanate (IPDI)).
  • the fibrous material may be chemically crosslinked, such as for example through irradiation (e.g. UV), thermal crosslinking, redox cross-linking, electron-beam cross-linking, etc.
  • the fibrous materials of the present invention further encompass an oligomeric or macromonomeric urethane-based cross-linker.
  • oligomer is meant to be a sequence of monomers which consists of a few repeating units, which is in contrast to polymers, wherein the number of monomers can be very high. Typical oligomers include dimers, trimers and tetramers, which are composed of 2, 3 and 4 monomers respectively. Oligomers are typically considered to comprise up to about 20 monomers.
  • the term “macromonomer” is a macromolecule with end-group which enable it to act as a monomer, such that each polymer or oligomer molecule contributes monomer units to a chain of the macromolecule.
  • said crosslinker has a backbone selected from the list comprising PEG, multi-(meth)acrylate, multi-(meth)acrylamide or a thiol-ene crosslinkable group; in particular said crosslinker is a cross-linkable urethane-based polymer (CUP) represented by formula (I), wherein PEG has a molecular weight of about 400 (CUP-PEG400) to about 2.000 (CUP-PEG2k).
  • CUP cross-linkable urethane-based polymer
  • the weight ratio of said CUP to crosslinker is between 90:10 and 60:40; preferably 90:10.
  • Particularly preferred combinations of CUPs are those having a high backbone molecular weight e.g. above 10k, and those having a low molecular weight e.g. less than 2k, of which the latter typically acts as a crosslinker. These combinations were found to be particularly suitable for electrospinning. In that aspect the following are particularly preferred: a) a fibrous material comprising:
  • CUP cross-linkable urethane-based polymer represented by formula (I), wherein PEG has a molecular weight of above 10000 g/mol;
  • CUP cross-linkable urethane-based polymer represented by formula (I), wherein PEG has a molecular weight of about 400 g/mol (CUP-PEG400) to about 2000 g/mol (CUP-PEG2k).
  • a fibrous material comprising:
  • CUP cross-linkable urethane-based polymer represented by formula (I), wherein PEG has a molecular weight of about 20000 g/mol (CUP-PEG20k);
  • CUP cross-linkable urethane-based polymer represented by formula (I), wherein PEG has a molecular weight of about 2000 g/mol (CUP-PEG2k).
  • the fibrous material of the present invention may further comprise an active agent.
  • active agents may for example be anti-bacterial agents in the event that materials are used in wound dressings, and textile.
  • Said active agent may also be a drug where the material is used as a carrier for drug delivery.
  • the fibrous materials of the present invention are suitable for numerous applications, including but not limited to hydrogels, in filtration devices, in affinity membranes, in (protective) clothing, in drug delivery systems, in tissue scaffolds,....
  • the present invention also provides a fibrous material as defined herein for use in human and/or veterinary medicine; more in particular for use in skin care and/or wound care; such as in particular for the treatment of wounds.
  • Table 1 Overview of material blends for electrospinning.
  • the electrospinning equipment mainly consists of a high voltage source (Glassman high voltage, Inc.; EL Series 40-45 Watt Regulated High Voltage DC Power Supplies), a motion controller (CWFW Universiteit Gent) and a pumping system (NE-1000 Programmable Single Syringe Pump).
  • the parameters used for electrospinning are presented in Table 2, the needle specifications are presented in Table 3.
  • Cross-linking of AUP was performed by UV curing by flushing in a UVA-transparent plastic bag to avoid interference of oxygen during crosslinking.
  • the electrospun fibers/mats were UV-cured by placing them between 2 high performance UV-A transilluminators manufactured by AppliTek NV, with wavelengths in the range of 315-400 nm for 1 hour.
  • the intensity of the upper and lower lamps was respectively 6.8mW/cm 2 and 6.2mW/cm 2 .
  • the electrospun fibers/mats Prior to UV-curing, the electrospun fibers/mats were put in UVA-transparent plastic bags and flushed with argon to avoid interference of oxygen during the UV-curing process. The intensity of both lamps was verified by measuring with a radiometer and probe UV-A (0-200 mW/cm 2 ), type RM12 manufactured by Opsytec Dr. Grobel.
  • a vacuum oven was used to dry the electrospun mats and remove any remaining solvent.
  • a Binder vacuum drying oven, model VD53 was used overnight at 40°C at a pressure lower than the vapour pressure of the solvent (73.6 mbar for water and 169.2 for ethanol, both at 40°C).
  • a cold trap is used to capture the vaporized solvent.
  • Results (and M&M ) to show the relevance of the crosslinker AUP PEG 20k can be electrospun as such. However, the material is mechanically too weak to be used for most applications. The addition of a crosslinker leads to a mechanically stronger material, whereby AUP PEG 2k resembles the AUP PEG 20k the most and leads to the least possibility of phase separation and as such the highest reproducibility.
  • Electrospinning of AUP PEG with a backbone MW up to 10kg/mol is difficult without the addition of a high MW PEG (1 M g/mol).
  • the addition of PEG 1 M g/mol results in a leachable compound after cross-linking of the fiber mat, causing a shrinkage of the mat or a possible deformation, for example with a mat of 10k + PEG 1 M g/mol.
  • high molecular weight AUP such as the AUP PEG 20k has a sufficient chain entanglement to be able to electrospin by itself. Therefore, in the context of the present invention, high molecular weight AUPs are preferred.

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Abstract

The present invention relates to the field of fibrous materials, more in particular comprising a cross-linkable urethane-based polymer (CUP) and an oligomeric or macromonomeric urethane- based cross-linker. The present invention also provides uses of such fibrous materials, such as for example as a hydrogel, in filtration devices, in affinity membranes, in (protective) clothing, in drug delivery systems, in tissue scaffolds, etc. It further provides the fibrous materials as defined herein for use in human and/or veterinary medicine, such as for use in skin and/or wound care.

Description

FIBROUS MATERIALS
FIELD OF THE INVENTION
The present invention relates to the field of fibrous materials, more in particular comprising a cross- linkable urethane-based polymer (CUP) and an oligomeric or macromonomeric urethane-based cross-linker. The present invention also provides uses of such fibrous materials, such as for example as a hydrogel, in filtration devices, in affinity membranes, in (protective) clothing, in drug delivery systems, in tissue scaffolds, etc. It further provides the fibrous materials as defined herein for use in human and/or veterinary medicine, such as for use in skin and/or wound care.
BACKGROUND TO THE INVENTION
In recent years, micro/nanomaterials have emerged as useful components in various applications, ranging from medical applications over environmental applications (e.g. filtration) even up to the use in safety devices, such as in (protective) clothing. The reason for this, is that micro/nanomaterials have unusual properties compared to macro-sized materials, due to their micro/nanoscale dimensions. In particular, they have extraordinary high surface area-to-volume ratios, and they can be tunable.
Micro/nanomaterials are often composed of fibers having micro/nanoscale diameters, in the form of micro/nanofibers. Such micro/nanofibers can be produced using a variety of techniques, including template synthesis, phase separation, self-assembly, electrospinning, etc.
Electrospinning is a particularly suitable fiber production method that uses electric forces to draw charged threads of polymer solutions or polymer melts up to fiber diameters in the order of some hundred micro/nanometers. The process does not require the use of coagulation chemistry or high temperatures to produce solid threads from solution. This makes the process particularly suited to the production of (micro/nano) fibers using large and complex molecules.
Micro/nanofiber matrices can have numerous applications particularly in the biomedical field such as for wound dressings or tissue scaffolds. Such electrospun dressings and scaffolds have exceptionally high surface areas and porosities because they are comprised of fibers with micro/nanoscale diameters, thereby enabling them to encourage superior cell infiltration, adhesion and efflux of liquids.
Electrospinning has the disadvantage however, that often toxic solvents are needed and that it is highly dependent on the starting materials to obtain the desired results. Starting materials that are particularly preferable for use in electrospinning (or other fiber production methods) should be processable, spinnable, non-shrinkable and stable. It is in particular difficult to select components having hydrogel properties, while still being easily processable and/or stabilized into fibers. It was thus an object of the present invention to provide a solution to the above-stated problems. Now, the inventors have surprisingly found that a cross-linkable urethane-based polymer (CUP) as defined herein in combination with an oligomeric or macromonomeric urethane-based cross-linker is particularly suitable in the preparation of fibrous materials via electrospinning, or other methods for preparing micro/nanofibers. It was specifically found that a combination of high molecular weight and low molecular weight CUPs is particularly suitable for said purpose.
SUMMARY OF THE INVENTION
In a first aspect, the present invention provides a fibrous material comprising:
- an oligomeric or macromonomeric urethane-based cross-linker; and
- a cross-linkable urethane-based polymer (CUP) represented by formula (I) wherein each occurrence of X and Y is independently a moiety comprising one or more of the following: acrylate groups, (multi)methacrylate groups, (multi)acrylate group, thiolactones and thiol-ene crosslinkable groups; each occurrence of Spacer is independently selected from the list comprising: oligo(ethylene oxide), oligo(propylene oxide), oligo(caprolactone), oligo(lactide) and oligo(glycolide); m and n are each independently from 1-6; p is from 1-10; and each occurrence of Backbone is independently selected from the list comprising poly(ethylene glycol) (PEG), poly(vinyl pyrrolidone) (PVP), poly(N-vinyl caprolactam) (PNVCL), poly(caprolactone) (PCL), poly(lactic acid) (PLA) or a combination thereof.
In a specific embodiment, the present invention provides a fibrous material comprising:
- an oligomeric or macromonomeric urethane-based cross-linker having a backbone molecular weight of less than or equal to 2000 g/mol; and
- a cross-linkable urethane-based polymer (CUP) represented by formula (I) and having a backbone molecular weight of above 2000 g/mol; wherein each occurrence of X and Y is independently a moiety comprising one or more of the following: acrylate groups, (multi)methacrylate groups, (multi)acrylate group, thiolactones and thiol-ene crosslinkable groups; each occurrence of Spacer is independently selected from the list comprising: oligo(ethylene oxide), oligo(propylene oxide), oligo(caprolactone), oligo(lactide) and oligo(glycolide); m and n are each independent from 1-6; p is from 1-10; and each occurrence of Backbone is independently selected from the list comprising poly(ethylene glycol) (PEG), poly(vinyl pyrrolidone) (PVP), poly(N-vinyl caprolactam) (PNVCL), poly(caprolactone) (POL), poly(lactic acid) (PLA) or a combination thereof.
In a particular embodiment of the present invention, at least one occurrence of said Backbone is PEG; in particular PEG having a molecular weight of above 10000 g/mol (PEG10k); more in particular PEG 12k, PEG20k, PEG35k or PEG40k; preferably PEG20k.
In another particular embodiment, said urethane-based crosslinker has a backbone selected from the list comprising PEG, multi-(meth)acrylate or multi-(meth)acrylamide or a thiol-ene crosslinkable group; in particular said crosslinker is a cross-linkable urethane-based polymer (CUP) represented by formula (I), wherein PEG has a molecular weight of about 400 g/mol (CUP-PEG400) to about 2000 g/mol (CUP-PEG2k).
In a further particular embodiment, the weight ratio of said CUP to crosslinker is between 90:10 and 60:40; preferably 90:10.
In a specific embodiment, the present invention provides a fibrous material comprising:
- a cross-linkable urethane-based polymer (CUP) represented by formula (I), wherein PEG has a molecular weight of above 10000 g/mol;
- as crosslinker, a cross-linkable urethane-based polymer (CUP) represented by formula (I), wherein PEG has a molecular weight of about 400 g/mol (CUP-PEG400) to about 2000 g/mol (CUP-PEG2k). In a very specific embodiment, the present invention provides a fibrous material comprising:
- a cross-linkable urethane-based polymer (CUP) represented by formula (I), wherein PEG has a molecular weight of about 20000 g/mol (CUP-PEG20k);
- as crosslinker, a cross-linkable urethane-based polymer (CUP) represented by formula (I), wherein PEG has a molecular weight of about 2000 g/mol (CUP-PEG2k).
In a further embodiment of the present invention, the weight ratio of said CUP-PEG20k to CUP- PEG2k is 90:10.
In another embodiment, the fibrous material of the present invention may further comprise an active agent.
In another embodiment, the fibrous material may be chemically crosslinked.
The present invention also provides the use of the fibrous material as defined herein; as a hydrogel, in filtration devices, in affinity membranes, in (protective) clothing, in drug delivery systems, in tissue scaffolds.
The present invention further provides the fibrous material as defined herein for use in human and/or veterinary medicine; in particular for use in skin care and/or wound care.
The present invention also provides a fibrous material as defined herein for use in human and/or veterinary medicine; more in particular for use in skin care and/or wound care.
DETAILED DESCRIPTION OF THE INVENTION
As already detailed herein above, the present invention provides a fibrous material comprising:
- an oligomeric or macromonomeric urethane-based cross-linker; and
- a cross-linkable urethane-based polymer (CUP) represented by formula (I) each occurrence of X and Y is independently a moiety comprising one or more of the following: acrylate groups, (multi)methacrylate groups, (multi)acrylate group, thiolactones and thiol-ene crosslinkable groups; each occurrence of Spacer is independently selected from the list comprising: oligo(ethylene oxide), oligo(propylene oxide), oligo(caprolactone), oligo(lactide) and oligo(glycolide); m and n are each independently from 1-6; p is from 1-10; and each occurrence of Backbone is independently selected from the list comprising poly(ethylene glycol) (PEG), poly(vinyl pyrrolidone) (PVP), poly(N-vinyl caprolactam) (PNVCL), poly(caprolactone) (POL), poly(lactic acid) (PLA) or a combination thereof.
In a specific embodiment, the present invention provides a fibrous material comprising:
- an oligomeric or macromonomeric urethane-based cross-linker having a backbone molecular weight of less than or equal to 2000 g/mol; and
- a cross-linkable urethane-based polymer (CUP) represented by formula (I) and having a backbone molecular weight of above 2000 g/mol wherein each occurrence of X and Y is independently a moiety comprising one or more of the following: acrylate groups, (multi)methacrylate groups, (multi)acrylate group, thiolactones and thiol-ene crosslinkable groups; each occurrence of Spacer is independently selected from the list comprising: oligo(ethylene oxide), oligo(propylene oxide), oligo(caprolactone), oligo(lactide) and oligo(glycolide); m and n are each independent from 1-6; p is from 1-10; and each occurrence of Backbone is independently selected from the list comprising poly(ethylene glycol) (PEG), poly(vinyl pyrrolidone) (PVP), poly(N-vinyl caprolactam) (PNVCL), poly(caprolactone) (POL), poly(lactic acid) (PLA) or a combination thereof.
In the context of the present invention, the term “urethane-based polymer” is meant to be a polymeric agent containing one or more carbamate or urethane links. A carbamate is an organic compound derived from carbamic acid (NH2COOH), and as such a carbamate link may be generally represented as follows: wherein each of said represents an attachment point to the remainder of the polymer molecule. In the context of the present invention, the claimed polymers contain at least one carbamate linker, however, they may also contain several carbamate linkers such as 2, 3, 4, or 5 carbamates.
The term “urethane- and/or urea-containing moiety” as used herein is meant to be a moiety composed of organic units joined by carbamate (urethane) links, i.e. -NH-(C=0)-0-; and/or urea links, i.e. -NH-(C=0)-NH-. Hence, in one embodiment, this moiety may contain only urethane linkers. Alternatively, this moiety may contain only urea linkers. Moreover, this moiety may also contain a combination of urethane and urea linkers.
As detailed herein above, the urethane-based polymers of the present invention may include different types and numbers of end-groups, including acrylate groups, (multi)methacrylate groups, (multi)acrylate group, thiolactones and thiol-ene crosslinkable groups. Alternatively, the urethane- based polymers may also include (meth)acrylamide groups. Hence, the compounds of the present invention may also be termed as such, for example, in the event of X and/or Y being selected as acrylate groups, the polymers may be termed acrylate end-capped urethane-based polymers (i.e. AUP).
Hence, in a specific embodiment, the present invention also provides an acrylate end-capped urethane-based polymer of formula (II)
In an alternative embodiment, the present invention also provides a urethane-based polymer of formula (I) wherein m, n, p, Spacer and Backbone are defined as herein above. Hence, each occurrence of crosslinkable urethane-based polymer (CUP) in the current application can be replaced by urethane-based polymer (UP).
The term “acrylate end-capped” as used herein means that the acrylate groups of the molecules of the invention are the polymer endgroups.
In the context of the present invention, the term “acrylate” is meant to include salts, esters and conjugate bases of acrylic acid and it derivatives. Acrylates contain vinyl groups, i.e. 2 carbon atoms double bonded to each other, directly attached to a carbonyl carbon. An acrylate moiety is typically represented as follows: wherein R represents -H in the event of acrylates or an alkyl group such as for example a methyl (-CH3) moiety, in the event of methacrylates. The (meth)acrylate groups according to the present invention are attached to the remainder of the polymer via the -O- linker, such that the double bonded carbon atom faces outwardly of the molecules.
In a specific embodiment, X and/or Y, may be selected to be a functional group that is able to or susceptible to thiol-ene cross-linking (i.e. a thiol-ene cross-linkable group). Preferably, the functional groups comprise functional groups able to or susceptible to thiol-ene crosslinking. The functional groups comprise for example meth(acrylate) functional groups, norbornene functional groups, vinyl ether functional groups, vinylester functional groups, allyl ether functional groups, propenyl ether functional groups and/or alkene functional groups and/or N-vinylamide functional groups. Particularly preferred functional groups comprise norbornene functional groups and/or vinylether functional groups.
The use of thiol-ene cross-linkable groups in the urethane-based polymers of the present invention, may be advantageous, since these can reduce the brittleness of the end products and result in a more homogeneous network formation.
In the context of the present invention, the term “spacer” is meant to be a moiety intended to provide a (flexible) hinge between 2 other elements of the molecule in which it is included, thereby spatially separating said elements. In the context of the present invention, a spacer may be present as indicated in Formula I. In the context of the invention, any type of suitable moiety may be used as a spacer, however, it is preferably selected from the list comprising oligo(ethylene oxide), oligo(propylene oxide), oligo(caprolactone), oligo(lactide) and oligo(glycolide):
Oligo(ethylene oxide) Oligo(propylene oxide) Oligo(caprolactone) wherein n is 1-6
Oligo(lactide) Oligo(glycolide)
Moreover, as evident from Formula I, the spacer is present on both sides of the molecule, in which m and n are independently selected from 1-6. This means that where a spacer is selected to be for example oligo(ethylene oxide) and n is for example 2, the spacer thus comprises 2 ethylene oxide moieties. Moreover, the left and right parts of the claimed molecules need not to be symmetrical, meaning that each spacer and the number of monomeric units within each spacer may be selected independently from each other. Nevertheless, in a preferred embodiment, the left and right parts of the claimed molecules are symmetrical, meaning that both sides of the molecule contain the same spacer containing the same number of monomeric units.
As evident from formula I, the claimed molecules also encompass a backbone, which may be selected from the list comprising: poly(ethylene glycol) (PEG), poly(vinyl pyrrolidone) (PVP), poly(n- vinyl caprolactam) (PNVCL), poly(lactic acid) (PLA), poly(caprolactone) (PCL) or a combination thereof: poly(lactic acid) (PLA) poly(caprolactone)
In a particular embodiment, the present invention provides a polymer combination of cross-linkable urethane-based polymers (CUPs) represented by formula (I) and/or formula (II); wherein at least one of said polymers has a backbone of PEG and at least one other polymer has a backbone of PVP, PNVCL, PLA, PCL or a combination thereof. In a particular embodiment, said polymer combination may be selected from a copolymer, a polymer blend, or a combination of different polymer layers (i.e. multilayer stack).
In the context of the present invention, the term “polymer blend” is meant to be a polymer mixture in which two or more polymers of a different nature are blended. In the context of the present invention, a copolymer is meant to be a polymeric molecule comprising at least 2 different types of monomeric subunits. This means that the present invention also provides a cross-linkable urethane- based polymer (CUP) represented by formula (I); wherein at least one part of said polymer has a backbone of PEG and at least one other part of said polymer has a backbone of PVP, PNVCL, PLA, PCL or a combination thereof.
In a specific embodiment of the present invention, the cross-linker is selected such as to have a low molecular weight, whereas the CUP is preferably having a higher molecular weight.
Accordingly, in a particular embodiment, said cross-linker has a molecular weight of less than or equal to 2000 g/mol; such as from about 400 g/mol to about 2000 g/mol; more specifically about 400 g/mol; about 500 g/mol; about 600 g/mol; about 700 g/mol; about 800 g/mol; about 900 g/mol; about 1000 g/mol; about 1100 g/mol; about 1200 g/mol; about 1300 g/mol; about 1400 g/mol; about 1500 g/mol; about 1600 g/mol; about 1700 g/mol; about 1800 g/mol; about 1900 g/mol; or about 2000 g/mol.
In another particular embodiment, said CUP has a molecular weight of above 2000 g/mol; such as about 4.000 g/mol; about 6.000 g/mol; about 8.000 g/mol; about 10.000 g/mol; about 12.000 g/mol, about 20.000 g/mol, about 35.000 g/mol, about 40.000 g/mol. Accordingly, where both the polymer and the crosslinker are selected to be a polymer of formula (I) and/or (II), the crosslinker is preferably having a low molecular weight, i.e. less than or equal to 2000 g/mol (e.g. 400 g/mol - 2000 g/mol) and the polymer is preferably having a high molecular weight, i.e. above 2000 g/mol (e.g. > 10000 g/mol, preferably > 20000 g/mol).
In another specific embodiment of the present invention, said backbone has a molecular weight of about 400 g/mol to about 40000 g/mol. Where both the polymer and the crosslinker are selected to be a polymer of formula (I) and/or (II), the crosslinker is preferably selected to have a backbone with a low molecular weight (e.g. 400 g/mol - 2000 g/mol) and the polymer is preferably selected to have a backbone with a high molecular weight (e.g. > 10000 g/mol, preferably > 20000 g/mol).
Where in the context of the present invention, the term molecular weight in respect of a polymer is used, this is meant to be the molecular weight of the backbone. Accordingly, where a polymer is said to have a molecular weight of above 2.000 g/mol; it is meant that the backbone of said polymer should have a molecular weight of above 2.000 g/mol.
In other words, the backbone of the polymers and if applicable the crosslinkers may be selected from any PEG, any PVP, any PNVCL, any PLA, any PCL or any combination thereof, such as a combination of PEG and PVP, a combination of PEG and PNVCL, a combination of PEG and PCL, a combination of PEG and PLA, etc. Each of said combinations may thus be in the form of a polymer blend, e.g. polymers having a PEG backbone blended together with polymers having a PVP backbone. Alternatively said combinations may be in the form of a copolymer, e.g. polymers having a PEG/PVP backbone; wherein some occurrences of Backbone are selected to be PEG and other occurrences of Backbone are selected to be PVP. The same reasoning also applies for other combinations of polymers e.g. PEG/PNVCL, PEG/PLA, PEG/PCL, etc.
In a particular embodiment of the present invention, at least one occurrence of said Backbone is PEG; in particular PEG having a molecular weight of above 10000 g/mol; more in particular PEG 12k, PEG20k, PEG35k or PEG40k; preferably PEG20k.
The advantage of the CUPs of the present invention is that they are electrospinnable. This is particularly advantageous in that these electrospun materials can be made in any kind of format, such as for example in the form of a sheet, a membrane, a fiber, a particle, a scaffold, etc. Electrospun materials provide an excellent environment to promote wound healing. Micro/nanofibers generated by the electrospinning technique offer a high surface-to-volume ratio, show good porosity levels, allow gaseous exchange and mimic the natural extra-cellular matrix. The formation of fibers via electrospinning depends on several parameters including but not limited to the viscosity, the needle-to-collector distance, the flow rate and the applied voltage, etc. These parameters influence the morphology of the obtained fibers. Cross-linkable urethane-based polymers (CUPs) are very interesting in this respect, due to their ability to cross-link upon Ultra-Violet (UV) irradiation in solid state. In addition, they exhibit high mechanical strength (up to 0.6 MPa in swollen state for precursors cross-linked in a 30 wt% aqueous solution) and biocompatibility. These hydrogel precursors can be based on different polymer backbones and cross-linking in the solid state is promoted by the presence of a flexible spacer which is linked to the backbone polymer by means of a di-isocyanate (such as for example isophorone di-isocyanate (IPDI)). In a particular embodiment, the fibrous material may be chemically crosslinked, such as for example through irradiation (e.g. UV), thermal crosslinking, redox cross-linking, electron-beam cross-linking, etc.
To promote cross-linking, the fibrous materials of the present invention further encompass an oligomeric or macromonomeric urethane-based cross-linker. In the context of the present invention the term “oligomer” is meant to be a sequence of monomers which consists of a few repeating units, which is in contrast to polymers, wherein the number of monomers can be very high. Typical oligomers include dimers, trimers and tetramers, which are composed of 2, 3 and 4 monomers respectively. Oligomers are typically considered to comprise up to about 20 monomers. In the context of the present invention, the term “macromonomer” is a macromolecule with end-group which enable it to act as a monomer, such that each polymer or oligomer molecule contributes monomer units to a chain of the macromolecule.
In a particular embodiment, said crosslinker has a backbone selected from the list comprising PEG, multi-(meth)acrylate, multi-(meth)acrylamide or a thiol-ene crosslinkable group; in particular said crosslinker is a cross-linkable urethane-based polymer (CUP) represented by formula (I), wherein PEG has a molecular weight of about 400 (CUP-PEG400) to about 2.000 (CUP-PEG2k).
In a further particular embodiment, the weight ratio of said CUP to crosslinker is between 90:10 and 60:40; preferably 90:10.
Particularly preferred combinations of CUPs, are those having a high backbone molecular weight e.g. above 10k, and those having a low molecular weight e.g. less than 2k, of which the latter typically acts as a crosslinker. These combinations were found to be particularly suitable for electrospinning. In that aspect the following are particularly preferred: a) a fibrous material comprising:
- a cross-linkable urethane-based polymer (CUP) represented by formula (I), wherein PEG has a molecular weight of above 10000 g/mol;
- as crosslinker, a cross-linkable urethane-based polymer (CUP) represented by formula (I), wherein PEG has a molecular weight of about 400 g/mol (CUP-PEG400) to about 2000 g/mol (CUP-PEG2k). b) a fibrous material comprising:
- a cross-linkable urethane-based polymer (CUP) represented by formula (I), wherein PEG has a molecular weight of about 20000 g/mol (CUP-PEG20k);
- as crosslinker, a cross-linkable urethane-based polymer (CUP) represented by formula (I), wherein PEG has a molecular weight of about 2000 g/mol (CUP-PEG2k).
In another embodiment, the fibrous material of the present invention may further comprise an active agent. Examples of such active agents may for example be anti-bacterial agents in the event that materials are used in wound dressings, and textile. Said active agent may also be a drug where the material is used as a carrier for drug delivery. Moreover, due to their tunable release properties, they are highly suitable for the controlled-release of such anti-microbial agents/drugs.
The fibrous materials of the present invention are suitable for numerous applications, including but not limited to hydrogels, in filtration devices, in affinity membranes, in (protective) clothing, in drug delivery systems, in tissue scaffolds,....
The present invention also provides a fibrous material as defined herein for use in human and/or veterinary medicine; more in particular for use in skin care and/or wound care; such as in particular for the treatment of wounds.
EXAMPLES
MATERIAL AND METHODS
Table 1 : Overview of material blends for electrospinning.
*AUP: Acrylate end-capped urethane-based polymers having a 2k or 20k PEG Backbone
Electrospinning set-up and parameters
The electrospinning equipment mainly consists of a high voltage source (Glassman high voltage, Inc.; EL Series 40-45 Watt Regulated High Voltage DC Power Supplies), a motion controller (CWFW Universiteit Gent) and a pumping system (NE-1000 Programmable Single Syringe Pump). The parameters used for electrospinning are presented in Table 2, the needle specifications are presented in Table 3.
Table 2: Optimized parameters used in electrospinning.
Table 3: Specifications of needles, made by Techcon Systems.
Cross-linking of AUP was performed by UV curing by flushing in a UVA-transparent plastic bag to avoid interference of oxygen during crosslinking.
The electrospun fibers/mats were UV-cured by placing them between 2 high performance UV-A transilluminators manufactured by AppliTek NV, with wavelengths in the range of 315-400 nm for 1 hour. The intensity of the upper and lower lamps was respectively 6.8mW/cm2 and 6.2mW/cm2. Prior to UV-curing, the electrospun fibers/mats were put in UVA-transparent plastic bags and flushed with argon to avoid interference of oxygen during the UV-curing process. The intensity of both lamps was verified by measuring with a radiometer and probe UV-A (0-200 mW/cm2), type RM12 manufactured by Opsytec Dr. Grobel.
A vacuum oven was used to dry the electrospun mats and remove any remaining solvent. A Binder vacuum drying oven, model VD53 was used overnight at 40°C at a pressure lower than the vapour pressure of the solvent (73.6 mbar for water and 169.2 for ethanol, both at 40°C). A cold trap is used to capture the vaporized solvent. RESULTS
1) Results (and M&M ) to show the relevance of the crosslinker AUP PEG 20k can be electrospun as such. However, the material is mechanically too weak to be used for most applications. The addition of a crosslinker leads to a mechanically stronger material, whereby AUP PEG 2k resembles the AUP PEG 20k the most and leads to the least possibility of phase separation and as such the highest reproducibility.
2) Results (and M&M) to show the relevance of selecting high molecular weight PEG over other PEGs
Electrospinning of AUP PEG with a backbone MW up to 10kg/mol is difficult without the addition of a high MW PEG (1 M g/mol). The addition of PEG 1 M g/mol results in a leachable compound after cross-linking of the fiber mat, causing a shrinkage of the mat or a possible deformation, for example with a mat of 10k + PEG 1 M g/mol. Interestingly, high molecular weight AUP, such as the AUP PEG 20k has a sufficient chain entanglement to be able to electrospin by itself. Therefore, in the context of the present invention, high molecular weight AUPs are preferred.

Claims

1. A fibrous material comprising:
- an oligomeric or macromonomeric urethane-based cross-linker having a backbone molecular weight of less than or equal to 2000 g/mol; and
- a cross-linkable urethane-based polymer (CUP) represented by formula (I) and having a backbone molecular weight of above 2000 g/mol wherein each occurrence of X and Y is independently a moiety comprising one or more of the following: acrylate groups, (multi)methacrylate groups, (multi)acrylate group, thiolactones and thiol-ene crosslinkable groups; each occurrence of Spacer is independently selected from the list comprising: oligo(ethylene oxide), oligo(propylene oxide), oligo(caprolactone), oligo(lactide) and oligo(glycolide); m and n are each independently from 1-6; p is from 1-10; and each occurrence of Backbone is independently selected from the list comprising polyethylene glycol (PEG), poly(vinyl pyrrolidone) (PVP), poly(N-vinyl caprolactam) (PNVCL), poly(caprolactone) (POL), poly(lactic acid) (PLA) or a combination thereof.
2. The fibrous material as defined in claim 1 ; wherein at least one occurrence of said Backbone is PEG.
3. The fibrous material as defined in anyone of claims 1 or 2; wherein at least one occurrence of said Backbone is PEG having a molecular weight of above 10000 g/mol; in particular PEG
12k, PEG20k, PEG35k or PEG40k.
4. The fibrous material as defined in anyone of claims 1 to 3; wherein said urethane-based crosslinker has a backbone selected from the list comprising PEG, multi-(meth)acrylate, multi- (meth)acrylamide and thiol-ene crosslinkable groups.
5. The fibrous material as defined in anyone of claims 1 to 4; wherein said cross-linker is a cross- linkable urethane-based polymer (CUP) represented by formula (I), wherein PEG has a molecular weight of about 400 g/mol (CUP-PEG400) to about 2000 g/mol (CUP-PEG2k).
6. The fibrous material as defined in anyone of claims 1 to 5, wherein the weight ratio of said CUP to crosslinker is between 90:10 and 60:40; preferably 90:10.
7. The fibrous material as defined in anyone of claims 1 to 6 comprising:
- a cross-linkable urethane-based polymer (CUP) represented by formula (I), wherein PEG has a molecular weight of above 10000 g/mol;
- as crosslinker, a cross-linkable urethane-based polymer (CUP) represented by formula (I), wherein PEG has a molecular weight of about 400 g/mol (CUP-PEG400) to about 2000 g/mol (CUP-PEG2k).
8. The fibrous material as defined in anyone of claims 1 to 7 comprising:
- a cross-linkable urethane-based polymer (CUP) represented by formula (I), wherein PEG has a molecular weight of about 20000 g/mol (CUP-PEG20k);
- as crosslinker, a cross-linkable urethane-based polymer (CUP) represented by formula (I), wherein PEG has a molecular weight of about 2000 g/mol (CUP-PEG2k).
9. The fibrous material as defined in claim 8, wherein the weight ratio of CUP-PEG20k to CUP- PEG2k is 90:10.
10. The fibrous material as defined in anyone of claims 1 to 9; further comprising an active agent.
11. The fibrous material as defined in anyone of claims 1 to 10; which is chemically crosslinked.
12. Use of the fibrous material as defined in anyone of claims 1 to 11 ; as a hydrogel, in filtration devices, in affinity membranes, in (protective) clothing, in drug delivery systems, in tissue scaffolds.
13. The fibrous material as defined in anyone of claims 1 to 11 for use in human and/or veterinary medicine.
14. The fibrous material as defined in anyone of claims 1 to 11 for use in skin care and/or wound care.
EP20771296.9A 2019-09-11 2020-09-11 Fibrous materials Active EP4028445B1 (en)

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US7750201B2 (en) * 2006-04-11 2010-07-06 Tyco Healthcare Group Lp Wound dressings with anti-microbial and chelating agents
EP2573215A1 (en) * 2011-09-20 2013-03-27 Mölnlycke Health Care AB Polymer fibers
EP3320008B1 (en) * 2015-07-08 2023-12-06 Universiteit Gent Novel urethane based materials, derivatives, methods of their preparation and uses

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